title: Paneth cells as a site of origin for intestinal inflammation.
abstract: The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.
authors.affiliation: 1] Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK [2].
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authors.lastname: Adolph
authors.forename: Michal F
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authors.lastname: Niederreiter
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authors.lastname: Ko
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authors.lastname: Böck
authors.forename: Eduardo
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authors.lastname: Martinez-Naves
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Markus
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authors.lastname: Tschurtschenthaler
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authors.lastname: Hartwig
authors.forename: Shuhei
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authors.lastname: Hosomi
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Flak
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cusick
authors.forename: Kenji
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authors.lastname: Kohno
authors.forename: Takao
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authors.lastname: Iwawaki
authors.forename: Susanne
authors.initials: S
authors.lastname: Billmann-Born
authors.forename: Tim
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authors.lastname: Raine
authors.forename: Richa
authors.initials: R
authors.lastname: Bharti
authors.forename: Ralph
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authors.lastname: Lucius
authors.forename: Mi-Na
authors.initials: MN
authors.lastname: Kweon
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authors.lastname: Marciniak
authors.forename: Augustine
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authors.lastname: Choi
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hagen
authors.forename: Stefan
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authors.lastname: Schreiber
authors.forename: Philip
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authors.lastname: Rosenstiel
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authors.lastname: Kaser
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D007249:Inflammation; D007410:Intestinal Diseases / Q000235:genetics / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology*; D051379:Mice; D019879:Paneth Cells / Q000473:pathology*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C532820:Atg16l1 protein, mouse; C103652:Elf2 protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse